This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project explores hippocampal control of dorsolateral prefrontal cortex (dlPFC) during working memory performance in nonhuman primates. We are using reversible inactivation techniques in combination with behavioral testing and PET imaging to test the hypothesis that the hippocampus modulates dorsolateral PFC function via the meso-limbic dopamine system (a circuit including the nucleus accumbens, ventral pallidum and ventral tegmental area (VTA)) in nonhuman primates. Specifically, we test the hypothesis that the ventral pallidum functions to tonically inhibit VTA neurons until inhibited by hippocampal evoked release from the nucleus accumbens. We are currently testing the 3 monkeys in the first set of experiments. The subjects have been trained and implanted and we are comparing the effects of muscimol vs. saline injections into the hippocampus while the monkeys are tested on the visual paired comparison task (VPC). Behavioral testing is followed by PET scanning under muscimol or saline. The second set of animals purchased last year has completed the first course of training and are about to be implanted. They will then be used to assess the role of the meso-limbic dopamine system as the intermediary between the hippocampus and dlPFC. We will modulate activity of the nucleus accumbens using the GABA-A antagonist bicuculline, the net result of which is to reduce dopamine release into the dlPFC, impairing working memory.